Compounds for the treatment of metabolic disorders

ABSTRACT

Agents useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, artherosclerosis and arteriosclerosis are disclosed. Formula (I) wherein n is 1 or 2; m is 0, 1, 2, 4 or 5; q is 0 or 1; t is 0 or 1; R 2  is alkyl from 1 to 3 carbon atoms; R 3  is hydrogen, halo, alkyl having from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms; A is phenyl, unsubstituted or substituted by or 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloaldyl having from 3 to 6 ring carbon atoms wherein the cycloaldyl is unsubstitited or one or two ring carbons are independently mono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compounds of formula (I) by a ring carbon; and R 1  is hydrogen or alkyl having 1 or 2 carbon atoms. Alternatively, when R 1  is hydrogen, the biologically active agent can be a pharmaceutically acceptable salt of the compound of Formula (I).

REFERENCE TO PRIOR APPLICATIONS

This is national phase under 35 U.S.C. §371 of International ApplicationNo. PCT/US2004/003718, having an international filing date of Feb. 9,2004. This application claims priority of U.S. Provisional ApplicationNo. 60/447,168, filed Feb. 13, 2003, the contents of which are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a major cause of morbidity and mortality.Chronically elevated blood glucose leads to debilitating complications:nephropathy, often necessitating dialysis or renal transplant;peripheral neuropathy; retinopathy leading to blindness; ulceration ofthe legs and feet, leading to amputation; fatty liver disease, sometimesprogressing to cirrhosis; and vulnerability to coronary artery diseaseand myocardial infarction.

There are two primary types of diabetes. Type I, or insulin-dependentdiabetes mellitus (IDDM) is due to autoimmune destruction ofinsulin-producing beta cells in the pancreatic islets. The onset of thisdisease is usually in childhood or adolescence. Treatment consistsprimarily of multiple daily injections of insulin, combined withfrequent testing of blood glucose levels to guide adjustment of insulindoses, because excess insulin can cause hypoglycemia and consequentimpairment of brain and other functions.

Type II, or noninsulin-dependent diabetes mellitus (NIDDM) typicallydevelops in adulthood. NIDDM is associated with resistance ofglucose-utilizing tissues like adipose tissue, muscle, and liver, to theactions of insulin. Initially, the pancreatic islet beta cellscompensate by secreting excess insulin. Eventual islet failure resultsin decompensation and chronic hyperglycemia. Conversely, moderate isletinsufficiency can precede or coincide with peripheral insulinresistance. There are several classes of drugs that are useful fortreatment of NIDDM: 1) insulin releasers, which directly stimulateinsulin release, carrying the risk of hypoglycemia; 2) prandial insulinreleasers, which potentiate glucose-induced insulin secretion, and mustbe taken before each meal; 3) biguanides, including metformin, whichattenuate hepatic gluconeogenesis (which is paradoxically elevated indiabetes); 4) insulin sensitizers, for example the thiazolidinedionederivatives rosiglitazone and pioglitazone, which improve peripheralresponsiveness to insulin, but which have side effects like weight gain,edema, and occasional liver toxicity; 5) insulin injections, which areoften necessary in the later stages of NIDDM when the islets have failedunder chronic hyperstimulation.

Insulin resistance can also occur without marked hyperglycemia, and isgenerally associated with atherosclerosis, obesity, hyperlipidemia, andessential hypertension. This cluster of abnormalities constitutes the“metabolic syndrome” or “insulin resistance syndrome”. Insulinresistance is also associated with fatty liver, which can progress tochronic inflammation (NASH; “nonalcoholic steatohepatitis”), fibrosis,and cirrhosis. Cumulatively, insulin resistance syndromes, including butnot limited to diabetes, underlie many of the major causes of morbidityand death of people over age 40.

Despite the existence of such drugs, diabetes remains a major andgrowing public health problem. Late stage complications of diabetesconsume a large proportion of national health care resources. There is aneed for new orally active therapeutic agents which effectively addressthe primary defects of insulin resistance and islet failure with feweror milder side effects than existing drugs.

Currently there are no safe and effective treatments for fatty liverdisease. Therefore such a treatment would be of value in treating thiscondition.

WO 02/100341 (Wellstat Therapeutics Corp.) discloses4-(3-2,6-Dimethylbenzyloxy)phenyl)butyric acid. WO 02/100341 does notdisclose any compounds within the scope of Formula I shown below, inwhich m is 0, 1, 2, 4, or 5.

SUMMARY OF THE INVENTION

This invention provides a biologically active agent as described below.This invention provides the use of the biologically active agentdescribed below in the manufacture of a medicament for the treatment ofinsulin resistance syndrome, diabetes, cachexia, hyperlipidemia, fattyliver disease, obesity, atherosclerosis or arteriosclerosis. Thisinvention provides methods of treating a mammalian subject with insulinresistance syndrome, diabetes, cachexia, hyperlipidemia, fatty liverdisease, obesity, atherosclerosis or arteriosclerosis comprisingadministering to the subject an effective amount of the biologicallyactive agent described below. This invention provides a pharmaceuticalcomposition comprising the biologically active agent described below anda pharmaceutically acceptable carrier.

The biologically active agent in accordance with this invention is acompound of Formula I:

wherein n is 1 or 2; m is 0, 1, 2, 4 or 5; q is 0 or 1; t is 0 or 1; R²is alkyl having from 1 to 3 carbon atoms; R³ is hydrogen, halo, alkylhaving from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbonatoms;A is phenyl, unsubstituted or substituted by 1 or 2 groups selectedfrom: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxyhaving 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkyl havingfrom 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted orone or two ring carbons are independently mono-substituted by methyl orethyl; or a 5 or 6 membered heteroaromatic ring having 1 or 2 ringheteroatoms selected from N, S and O and the heteroaromatic ring iscovalently bound to the remainder of the compound of formula I by a ringcarbon; andR¹ is hydrogen or alkyl having 1 or 2 carbon atoms. Alternatively, whenR¹ is hydrogen, the biologically active agent can be a pharmaceuticallyacceptable salt of the compound of Formula I.

The biologically active agents described above have activity in one ormore of the biological activity assays described below, which areestablished animal models of human diabetes and insulin resistancesyndrome. Therefore such agents would be useful in the treatment ofdiabetes and insulin resistance syndrome. All of the exemplifiedcompounds that were tested demonstrated activity in at least one of thebiological activity assays in which they were tested.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein the term “alkyl” means a linear or branched-chain alkylgroup. An alkyl group identified as having a certain number of carbonatoms means any alkyl group having the specified number of carbons. Forexample, an alkyl having three carbon atoms can be propyl or isopropyl;and alkyl having four carbon atoms can be n-butyl, 1-methylpropyl,2-methylpropyl or t-butyl.

As used herein the term “halo” refers to one or more of fluoro, chloro,bromo, and iodo.

As used herein the term “perfluoro” as in perfluoromethyl orperfluoromethoxy, means that the group in question has fluorine atoms inplace of all of the hydrogen atoms.

As used herein “Ac” refers to the group CH₃C(O)—.

Certain chemical compounds are referred to herein by their chemical nameor by the two-letter code shown below. Compounds CF through CM areincluded within the scope of Formula I shown above.

-   BI 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid-   BT 4-[[4-(2,6-Dimethylbenzyloxy)-3-methoxy]phenyl]-4-oxobutyric acid-   BU    4-[3-[[N-(4-Trifluoromethylbenzyl)aminocarbonyl]-4-methoxy]phenyl]-4-oxobutyric    acid-   BV    4-[3-[[N-(2,6-dimethylbenzyl)aminocarbonyl]-4-methoxy]phenyl]-4-oxobutyric    acid-   CA (2,6-Dimethylbenzyloxy)benzene-   CB Methyl 3-(3-(2,6-Dimethylbenzyloxy)phenyl)-3-oxopropionate-   CC 3-(3-(2,6,-Dimethylbenzyloxy)phenyl)-4-oxobutyramide-   CD 5-(3-(2,6-Dimethylbenzyloxy)phenyl)-5-oxopentanoic acid-   CE 4-(3-(2,6-Dimethylbenzyloxy)phenyl)butyric acid-   CF 3-(2,6-Dimethylbenzyloxy)phenylacetic acid-   CG 3-(2,6-Dimethylbenzyloxy)benzoic acid-   CH Ethyl 3-(2,6-dimethylbenzyloxy)benzoate-   CI 6-[3-(2,6-Dimethylbenzyloxy)-phenyl]-hexanoic acid-   CJ Ethyl 6-[3-(2,6-dimethylbenzyloxy)-phenyl]-hexanoate-   CK 5-[3-(2,6-Dimethylbenzyloxy)-phenyl]-pentanoic acid-   CL Ethyl 5-[3-(2,6-dimethylbenzyloxy)-phenyl]-pentanoate-   CM 3-[3-(2,6-dimethylbenzyloxy)phenyl]-propionic acid-   CN Ethyl 3-[3-(2,6-dimethylbenzyloxy)phenyl]-propanoate

As used herein the transitional term “comprising” is open-ended. A claimutilizing this term can contain elements in addition to those recited insuch claim.

Compounds of the Invention

In an embodiment of the agent, use, method or pharmaceutical compositiondescribed above, n is 1; q is 0; t is 0; R³ is hydrogen; and A isphenyl, unsubstituted or substituted by 1 or 2 groups selected from:halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1or 2 carbon atoms, and perfluoromethoxy. In a more specific embodiment,A is 2,6-dimethylphenyl. Examples of such compounds include3-(2,6-Dimethylbenzyloxy)phenylacetic acid;3-(2,6-Dimethylbenzyloxy)benzoic acid; Ethyl3-(2,6-dimethylbenzyloxy)benzoate;6-[3-(2,6-Dimethylbenzyloxy)-phenyl]-hexanoic acid; Ethyl6-[3-(2,6-dimethylbenzyloxy)-phenyl]-hexanoate;5-[3-(2,6-Dimethylbenzyloxy)-phenyl]-pentanoic acid; Ethyl5-[3-(2,6-dimethylbenzyloxy)phenyl]-pentanoate;3-[3-(2,6-dimethylbenzyloxy)phenyl]-propionic acid; and Ethyl3-[3-(2,6-dimethylbenzyloxy)phenyl]-propanoate.

In a preferred embodiment of the biologically active agent of thisinvention, the agent is in substantially (at least 98%) pure form.

Reaction Schemes

The biologically active agents of the present invention can be made inaccordance with the following reaction schemes.

The compound of formula I where m is 0 to 2, q is 0, t is 0 or 1, and nis 1 or 2, R³ is hydrogen, halo, alkoxy having from 1 to 3 carbon atomsor alkyl having from 1 to 3 carbon atoms, and R¹ is hydrogen or alkylhaving from 1 to 2 carbon atoms, i.e. compounds of formula:

wherein A is described as above, can be prepared via reaction of scheme1.

In the reaction scheme of Scheme 1, A, t, n, m, and R³ are as above. R⁴is alkyl group having 1 to 2 carbon atoms, and Y is a leaving group.

The compound of formula II is converted to the compound of formula V viareaction of step (a) using Mitsunobu condensation of II with Im usingtriphenylphosphine and diethyl azodicarboxylate or diisopropylazodicarboxylate. The reaction is carried out in a suitable solvent forexample tetrahydrofuran. Any of the conditions conventionally used inMitsunobu reactions can be utilized to carry out the reaction of step(a).

The compound of formula V can also be prepared by etherifying oralkylating the compound of formula II with a compound of formula IV asin reaction of step (a). In the compound of formula IV, Y, include butare not limited to mesyloxy, tosyloxy, chloro, bromo, iodo, and thelike. Any conventional method of etherifying of a hydroxyl group byreaction with a leaving group can be utilized to carry out the reactionof step (a).

The compound of formula V is the compound of formula I where R¹ is alkylgroup having from 1 to 2 carbon atoms. The compound of formula V can beconverted to the free acid i.e. the compound of formula I where R¹ is Hby ester hydrolysis. Any conventional method of ester hydrolysis willproduce the compound of formula I where R¹ is H.

The compound of formula I where m is 3 to 5, q is 0, t is 0 or 1, and nis 1 or 2, R³ is hydrogen, halo, alkoxy having from 1 to 3 carbon atomsor alkyl having from 1 to 3 carbon atoms, and R¹ is hydrogen or alkylhaving from 1 to 2 carbons, i.e. compounds of formula:

wherein A is described as above, can be prepared via reaction of scheme2.

In the reaction scheme of Scheme 2, A, t, n, m, R¹ and R³ are as above.R⁴ is alkyl having from 1 to 2 carbon atoms, p is 1 to 3 and Y is aleaving group.

The compound of formula VI is converted to the compound of formula VIIvia reaction of step (b) using Mitsunobu condensation of VI with IIIusing triphenylphosphine and diethyl azodicarboxylate or diisopropylazodicarboxylate. The reaction is carried out in a suitable solvent forexample tetrahydrofuran. Any of the conditions conventionally used inMitsunobu reactions can be utilized to carry out the reaction of step(b).

The compound of formula VII can also be prepared by etherifying oralkylating the compound of formula VI with a compound of formula IV viathe reaction of step (c) by using suitable base such as potassiumcarbonate, sodium hydride, triethylamine, pyridine and the like. In thecompound of formula IV, Y, include but are not limited to mesyloxy,tosyloxy, chloro, bromo, iodo, and the like. Any conventional conditionsto alkylate a hydroxyl group with a halide or leaving group can beutilized to carry out the reaction of step (c). The reaction of step (c)is preferred over step (b) if compound of formula IV is readilyavailable.

The compound of formula VII is converted to the compound of formula IXvia reaction of step (d) by alkylating the compound of formula VII withthe compound of formula VIII. This reaction is carried out in thepresence of approximately a molar equivalent of a conventional base thatconverts acetophenone to 3-keto ester (i.e. gamma-keto ester). Incarrying out this reaction it is generally preferred but not limited toutilize alkali metal salts of hexamethyldisilane such as lithiumbis-(trimethylsilyl)amide and the like. Generally this reaction iscarried out in inert solvents such as tetrahydrofuran:1,3-Dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone. Generally thereaction is carried out at temperatures of from −65° C. to 25° C. Any ofthe conditions conventional in such alkylation reactions can be utilizedto carry out the reaction of step (d).

The compound of formula IX is converted to the free acid by esterhydrolysis. Any conventional method of ester hydrolysis will produce thecompound of formula IX where R¹ is H.

The compound of formula IX is converted to the compound of X viareaction of step (e) by reducing the ketone group to CH₂ group. Thereaction is carried out by heating compound of formula IX with hydrazinehydrate and a base such as KOH or NaOH in suitable solvent such asethylene glycol. In carrying out this reaction it is generally preferredbut not limited to utilize KOH as base. Any of the conditionsconventionally used in Wolff-Kishner reduction reactions can be utilizedto carry out the reaction of step (e). The compound of formula X is thecompound of formula I where R¹ is H.

In the compound of formula X, acid can be converted to ester i.e. thecompound of formula I where R¹ is alkyl having from 1 to 2 carbon atomsby esterification of acid by using catalysts for example H₂SO₄, TsOH andthe like or by using dehydrating agents for exampledicyclohexylcarbodiimide and the like in ethanol or methanol. Anyconventional conditions in such esterification reactions can be utilizedto produce the compound of formula I where R¹ is alkyl having from 1 to2 carbon atoms.

The compound of formula I where q is 1, R² is an alkyl group having 1 to3 carbon atoms, m is 3 to 5, t is 0 or 1 and n is 1 or 2, i.e. compoundsof the formula:

wherein A is described as above, R¹ is hydrogen or alkyl having from 1to 2 carbon atoms, R³ is hydrogen, halo, alkoxy having from 1 to 3carbon atoms or alkyl having from 1 to 3 carbon atoms, can be preparedvia the reaction scheme of Scheme 3.

In the reaction scheme of Scheme 3, t, n, A, R¹, R³, and R² are asabove. R⁴ is alkyl group having from 1 to 2 carbon atoms. Y is chloro orbromo and p is 1 to 3.

The compound of formula XI can be mesylated to furnish the compound offormula XII via reaction of step (f). Any conventional conditions tocarry out the mesylation reaction of a hydroxyl group can be utilized tocarry out the step (f). The compound of formula XII is then heated withthe compound of formula XI to produce the compound of formula XIV. Anyof the conditions conventional to produce amino alcohol can be utilizedto carry out the reaction of step (g).

In the compound of formula XIV, alcohol can be displaced by chloro orbromo by treating the compound of formula XIV with thionyl chloride,bromine, and phosphorus tribromide and the like to produce the compoundof formula XV. Any conventional method to displace alcohol with chloroor bromo can be utilized to carry out the reaction of step (h).

The compound of formula XV can be reacted with the compound of formulaVI via reaction of step (i) in the presence of a suitable base such aspotassium carbonate, sodium hydride, triethylamine and the like. Thereaction is carried out in conventional solvents such asdimethylformamide, tetrahydrofuran and the like to produce thecorresponding compound of formula XVI. Any conventional method ofetherification of a hydroxyl group in the presence of base (preferredbase being potassium carbonate) with chloro or bromo can be utilized tocarry out the reaction of step (i).

The compound of formula XVI can be converted to the compound of formulaXVII via reaction of step (j) by alkylating the compound of formula XVIwith the compound of formula VIII. This reaction is carried out in thepresence of approximately a molar equivalent of a suitable base such aslithium hexamethyldisilane. This reaction is carried out in the samemanner as described in connection with the reaction of step (d) ofScheme 2.

The compound of formula XVII can be converted to the free acid by esterhydrolysis. Any conventional method of ester hydrolysis will produce thecompound of formula XVII where R¹ is H.

The compound of formula XVII can be converted to the compound of XVIIIvia reaction of step (k) by reducing the ketone group to CH₂ group. Thereaction can be carried out by heating compound of formula XVII withhydrazine hydrate and base such as KOH or NaOH in suitable solvent suchas ethylene glycol. In carrying out this reaction it is generallypreferred but not limited to utilize KOH as base. Any of the conditionsconventionally used in Wolff-Kishner reduction reactions can be utilizedto carry out the reaction of step (k).

The compound of formula XVIII is the compound of formula I where R¹ isH.

In the compound of formula XVIII, acid can be converted to ester i.e.the compound of formula I where R¹ is alkyl having from 1 to 2 carbonatoms by esterification of acid by using catalysts for example H₂SO₄,TsOH and the like or by using dehydrating agents for exampledicyclohexylcarbodiimide and the like in ethanol or methanol. Anyconventional conditions in such esterification reactions can be utilizedto produce the compound of formula I where R¹ is alkyl having from 1 to2 carbon atoms.

The compound of formula I where m is 0 to 2, q is 1, t is 0 or 1, and nis 1 or 2, R³ is hydrogen, halo, alkoxy having from 1 to 3 carbon atomsor alkyl having from 1 to 3 carbon atoms, and R¹ is hydrogen or alkylhaving from 1 to 2 carbons, i.e. compounds of formula:

wherein A is described as above, can be prepared via reaction of Scheme4.

In the reaction of Scheme 4, t, n, A, R³, and R² are as above. R⁴ isalkyl group having from 1 to 2 carbon atoms. Y is chloro or bromo.

The compound of formula XV (prepared in the same manner as described inthe reaction of scheme 3) can be reacted with a compound of formula IIvia reaction of step (l) in the presence of a suitable base such aspotassium carbonate, sodium hydride, triethylamine and the like. Thereaction can be carried out in conventional solvents such asdimethylformamide, tetrahydrofuran, dichloromethane and the like toproduce the corresponding compound of formula XIX. Any conventionalconditions of etherification of a hydroxyl group in the presence of base(preferred base being potassium carbonate) with chloro or bromo can beutilized to carry out the reaction of step (l).

The compound of formula XIX is the compound of formula I where R¹ isalkyl group having from 1 to 2 carbon atoms. The compound of formula XIXcan be converted to the free acid i.e. the compound of formula I whereR¹ is H by ester hydrolysis. Any conventional method of ester hydrolysiswill produce the compound of formula I where R¹ is H.

The compound of formula 1 ml, where t is 0 or 1, n is 1 or 2, i.e.compounds of formula:A(CH₂)_(t+n)—OHwherein A is described as above, can be prepared via reaction of scheme5.

In the reaction of Scheme 5, A is described as above and Y is a leavinggroup.

The compound of formula XX can be reduced to the compound of formula XXIvia reaction of step (m). The reaction is carried out utilizing aconventional reducing agent for example alkali metal hydride such aslithium aluminum hydride. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran. Any of the conditions conventional insuch reduction reactions can be utilized to carry out the reaction ofstep (m).

The compound of formula XXI is the compound of formula III where t is 0and n is 1.

The compound of formula XXI can be converted to the compound of formulaXXII by displacing hydroxyl group with a halogen group preferred halogenbeing bromo or chloro. Appropriate halogenating reagents include but arenot limited to thionyl chloride, bromine, phosphorous tribromide, carbontetrabromide and the like. Any conditions conventional in suchhalogenation reactions can be utilized to carry out the reaction of step(n).

The compound of formula XXII is the compound of formula IV where t is 0and n is 1.

The compound of formula XXII can be converted to the compound of formulaXXII by reacting XXII with an alkali metal cyanide for example sodium orpotassium cyanide. The reaction is carried out in a suitable solvent,such as dimethyl sulfoxide. Any of the conditions conventionally used inthe preparation of nitrile can be utilized to carry out the reaction ofstep (O).

The compound of formula XXIII can be converted to the compound offormula XXIV via reaction step (p) by acid or base hydrolysis. Incarrying out this reaction it is generally preferred to utilize basichydrolysis, for example aqueous sodium hydroxide. Any of the conditionsconventionally used in hydrolysis of nitrile can be utilized to carryout the reaction of step (p).

The compound of formula XXIV can be reduced to give the compound offormula XXV via reaction of step (q). This reaction can be carried outin the same manner as described hereinbefore in the reaction of step(m).

The compound of formula XXV is the compound of formula III where t is 1and n is 1.

The compound of formula XXV can be converted to the compound of formulaXXVI via reaction of step (r) in the same manner as describedhereinbefore in connection with the reaction of step (n).

The compound of formula XXVI is the compound of formula IV where t is 1and n is 1.

The compound of formula XXVI can be reacted with diethyl malonateutilizing a suitable base for example sodium hydride to give compound offormula XXVII. The reaction is carried out in suitable solvents, such asdimethylformamide, tetrahydrofuran and the like. Any of the conditionsconventional in such alkylation reactions can be utilized to carry outthe reaction of step (s).

The compound of formula XXVII can be hydrolyzed by acid or base to givecompound of formula XXVII via reaction of step (t).

The compound of formula XXVIII can be converted to the compound offormula XXIX via reaction of step (u) in the same manner as describedhereinbefore in connection with the reaction of step (m).

The compound of formula XXIX is the compound of formula III where t is 1and n is 2.

The compound of formula XXIX can be converted to the compound of formulaXXX via reaction of step (v) in the same manner as describedhereinbefore in connection with the reaction of step (n). The compoundof formula XXX is the compound of formula IV where t is 1 and n is 2.

The compound of formula II, where m is 0, R⁴ is alkyl group having from1 to 2 carbon atoms and R³ is halo, alkoxy having from 1 to 3 carbonatoms or alkyl having from 1 to 3 carbon atoms, i.e. compounds offormula:

can be prepared via reaction of scheme 6.

In the reaction of Scheme 6, R¹ is H. R³ and R⁴ are as above.

In the compound of formula XXXI, R¹ is H. The compound of formula XXXIcan be converted to the compound of formula II via reaction of step (w)by esterification of compound of formula XXXI with methanol or ethanol.The reaction can be carried out either by using catalysts for exampleH₂SO₄, TsOH and the like or by using dehydrating agents for exampledicyclohexylcarbodiimide and the like. Any of the conditionsconventional in such esterification reactions can be utilized to carryout the reaction of step (w).

The compound of formula VI where R³ is halo, alkoxy having from 1 to 3carbon atoms or alkyl having from 1 to 3 carbon atoms, i.e. compounds offormula:

can be prepared via reaction of scheme 7.

In the reaction of Scheme 7, m is 0 and R¹ is H and R³ is halo, alkoxyhaving from 1 to 3 carbon atoms or alkyl having from 1 to 3 carbonatoms.

In Reaction Scheme 7 m is 0. Reaction Scheme 7 is analogous to themethod of George M Rubottom et al., J. Org. Chem. 1983, 48, 1550-1552.

The compound of formula II where m is 1 to 2, R⁴ is alkyl group havingfrom 1 to 2 carbon atoms and R³ is halo, alkoxy having from 1 to 3carbon atoms or alkyl having from 1 to 3 carbon atoms, i.e. compounds offormula:

can be prepared via reaction of scheme 8.

In the reaction of Scheme 8, R¹ is H, R³ is halo, alkoxy having from 1to 3 carbon atoms or alkyl having from 1 to 3 carbon atoms, R⁴ is alkylgroup having 1 to 2 carbon atoms and R⁵ is a hydroxy protecting group.

The compound of formula II where m is 0 can be converted to the compoundof formula XXXII via reaction of step (y) first by protecting thehydroxy group by utilizing suitable protecting groups such as thosedescribed in Protecting Groups in Organic Synthesis by T. Greene andthen by deprotecting the ester group by ester hydrolysis. Anyconventional method of ester hydrolysis will produce the compound offormula XXXI where R¹ is H.

The compound of formula XXXII can be reduced to the compound of formulaXXXIII by utilizing conventional reducing reagent that converts acid toan alcohol via reaction of step (z). In carrying out this reaction it isgenerally preferred but not limited to utilize lithium aluminum hydride.The reaction is carried out in a suitable solvent such astetrahydrofuran and the like. Any of the conditions conventional in suchreduction reactions can be utilized to carry out the reaction of step(z).

The compound of formula XXXIII can be converted to the compound offormula XXXIV by displacing hydroxy group with a halogen preferredhalogen being bromo or chloro. Appropriate halogenating reagents includebut are not limited to thionyl chloride, bromine, phosphoroustribromide, carbon tetrabromide and the like. Any conditionsconventional in such halogenation reactions can be utilized to carry outthe reaction of step (a′).

The compound of formula XXXIV can be converted to the compound offormula XXXV by reacting XXXIV with an alkali metal cyanide for examplesodium or potassium cyanide. The reaction is carried out in a suitablesolvent such as dimethyl sulfoxide. Any of the conditions conventionallyused in the preparation of nitrites can be utilized to carry out thereaction of step (b′).

The compound of formula XXXV can be converted to the compound of formulaXXXVI via reaction step (c′) by acid or base hydrolysis. In carrying outthis reaction, it is generally preferred to utilize basic hydrolysis,for example aqueous sodium hydroxide. Any of the conditions conventionalfor the hydrolysis of nitrile can be utilized to carry out the reactionof step (c′).

The compound of formula XXXVI can be converted to the compound offormula XXXVII via reaction of step (d′) by removal of hydroxyprotecting group utilizing suitable deprotecting reagents such as thosedescribed in Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula XXXVII can be converted to compound of formulaII where m is 1 and R⁴ is alkyl group having from 1 or 2 carbon atoms byesterification of compound of formula XXXVII with methanol or ethanol.The reaction can be carried out either by using catalysts for exampleH₂SO₄, TsOH and the like or by using dehydrating agents for exampledicyclohexylcarbodiimide and the like. Any of the conditionsconventional in such esterification reactions can be utilized to carryout the reaction.

The compound of formula XXXIV can be reacted with diethyl malonateutilizing a suitable base for example sodium hydride to give compound offormula XXXVIII. The reaction is carried out in suitable solvents, suchas dimethylformamide, tetrahydrofuran and the like. Any of theconditions conventional in such alkylation reactions can be utilized tocarry out the reaction of step (e′).

The compound of formula XXXVIII can be hydrolyzed by acid or base andremoval of hydroxy protecting group utilizing suitable deprotectingreagents su-ch as those described in Protecting Groups in OrganicSynthesis by T. Greene to give compound of formula XXXIX via reaction ofstep (f′).

The compound of formula XXXIX can be converted to the compound offormula II where m is 2 and R⁴ is alkyl group having from 1 or 2 carbonatoms by esterification of compound of formula XXXIX with methanol orethanol. The reaction can be carried out either by using catalysts forexample H₂SO₄, TsOH and the like or by using dehydrating agents forexample dicyclohexylcarbodiimide and the like. Any of the conditionsconventional in such esterification reactions can be utilized to carryout the reaction.

The compound of formula XXXI, where m is 0, R¹ is H and R³ is halo, i.e.compounds of formula:

are either commercially available or can be prepared according to themethods described in the literature as follows:

-   1. 3-Br or F-2-OHC₆H₃CO₂H-   Canadian Journal of Chemistry (2001), 79(11) 1541-1545.-   2. 4-Br-2-OHC₆H₃CO₂H-   WO 9916747 or JP 04154773.-   3. 2-Br-6-OHC₆H₃CO₂H-   JP 47039101.-   4. 2-Br-3-OHC₆H₃CO₂H-   WO 9628423.-   5. 4-Br-3-OHC₆H₃CO₂H-   WO 2001002388.-   6. 3-Br-5-OHC₆H₃CO₂H-   Journal of labelled Compounds and Radiopharmaceuticals (1992), 31    (3), 175-82.-   7. 2-Br-5-OHC₆H₃CO₂H and 3-Cl-4-OHC₆H₃CO₂H-   WO 9405153 and U.S. Pat. No. 5,519,133.-   8. 2-Br-4-OHC₆H₃CO₂H and 3-Br-4-OHC₆H₃CO₂H-   WO 20022018323-   9. 2-Cl-6-OHC₆H₃CO₂H-   JP 06293700-   10. 2-Cl-3-OHC₆H₃CO₂H-   Proceedings of the Indiana Academy of Science (1983), Volume date    1982, 92, 145-51.-   11. 3-Cl-5-OHC₆H₃CO₂H-   WO 2002000633 and WO 2002044145.-   12. 2-Cl-5-OHC₆H₃CO₂H-   WO 9745400.-   13. 5-I-2-OHC₆H₃CO₂H and 3-I, 2-OHC₆H₃CO₂H-   Z. Chem. (1976), 16(8), 319-320.-   14. 4-I-2-OHC₆H₃CO₂H-   Journal of Chemical Research, Synopses (1994), (11), 405.-   15. 6-I-2-OHC₆H₃CO₂H-   U.S. Pat. No. 4,932,999.-   16. 2-I-3-OHC₆H₃CO₂H and 4-I-3-OHC₆H₃CO₂H-   WO 9912928.-   17. 5-I-3-OHC₆H₃CO₂H-   J. Med. Chem. (1973), 16(6), 684-7.-   18. 2-I-4-OHC₆H₃CO₂H-   Collection of Czechoslovak Chemical Communications, (1991), 56(2),    459-77.-   19. 3-I-4-OHC₆H₃CO₂,-   J.O.C. (1990), 55(18), 5287-91.

The compound of formula XXXI, where m is 0, R¹ is H and R³ is alkoxyhaving from 1 to 3 carbon atoms, and the phenyl ring is substituted asshown below:

can be synthesized via the reaction of scheme 9.

In the reaction of Scheme 9, R¹ and R³ are as above, and R⁴ is alkylgroup having from 1 to 2 carbon atoms.

The compound of formula XL can be converted to the compound of formulaXLI by reducing aldehyde to primary alcohol. In carrying out thisreaction, it is preferred but not limited to use sodium borohydride asthe reducing reagent. Any of the conditions suitable in such reductionreactions can be utilized to carry out the reaction of step (g′).

The compound of formula XLI can be converted to the compound of formulaXLII via reaction of step (h′) by protecting 1-3 Diols by using1,1,3,3-Tetraisopropyldisiloxane. The suitable conditions for thisprotecting group can be described in the Protecting Groups in OrganicSynthesis by T. Greene.

The compound of formula XLII can be converted to the compound of formulaXLIII via reaction of step (i′) by protecting phenol group by usingbenzyl bromide. The suitable conditions for this protecting group can bedescribed in the Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula XLIII can be converted to the compound offormula XLIV by deprotection using tetrabutylammonium fluoride viareaction of step (j′). The suitable conditions for the deprotection canbe described in the Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula XLIV can be converted to compound of formula XLVvia reaction of step (k′) by oxidation. Any conventional oxidizing groupthat converts primary alcohol to an acid for example chromium oxide andthe like can be utilized to carry out the reaction of step (k′).

The compound of formula XLV can be converted to the compound of formulaXLVI by esterification of compound of formula XLV with methanol orethanol. The reaction can be carried out either by using catalysts forexample H₂SO₄, TsOH and the like or by using dehydrating agents forexample dicyclohexylcarbodlinide and the like. Any of the conditionsconventional in such esterification reactions can be utilized to carryout the reaction of step (l′).

The compound of formula XLVI can be converted to the compound of formulaXLVII by etherifying or alkylating the compound of formula XLVI withmethyl halide or ethyl halide or propyl halide by using suitable basefor example potassium carbonate, sodium hydride and the like. Thereaction is carried out in conventional solvents, such asterahydrofuran, dimethylformamide. The reaction is generally carried outat temperatures of from 0° C. to 40° C. Any of the conditions suitablein such alkylation reactions can be utilized to carry out the reactionof step (m′).

The compound of formula XLVII can be converted to the compound offormula XLVIII by deprotection of ester and benzyl groups. The suitabledeprotecting conditions can be described in the Protecting Groups inOrganic Synthesis by T. Greene.

Other compounds of formula XXXI where m is 0, R¹ is H and R³ is alkoxyhaving from 1 to 3 carbon atoms, i.e. compounds of formula:

are either commercially available or can be prepared according to themethods described in the literature as follows:

-   1. 2-OMe-4-OHC₆H₃CO₂H-   US 2001034343 or WO 9725992.-   2. 5-OMe-3-OHC₆H₃CO₂H-   J.O.C (2001), 66(23), 7883-88.-   3. 2-OMe-5-OHC₆H₃CO₂H-   U.S. Pat. No. 6,194,406 (Page 96) and Journal of the American    Chemical Society (1985), 107(8), 2571-3.-   4. 3-OEt-5-OHC₆H₃CO₂H-   Taiwan Kexue (1996), 49(1), 51-56.-   5. 4-OEt-3-OHC₆H₃CO₂H-   WO 9626176-   6. 2-OEt-4-OHC₆H₃CO₂H-   Takeda Kenkyusho Nempo (1965), 24,221-8.-   JP 07070025.-   7. 3-OEt-4-OHC₆H₃CO₂H-   WO 9626176.-   8. 3-OPr-2-OHC₆H₃CO₂H-   JP 07206658, DE 2749518.-   9. 4-OPr-2-OHC₆H₃CO₂H-   Farmacia (Bucharest) (1970), 18(8), 461-6.-   JP 08119959.

10. 2-OPr-5-OHC₆H₃CO₂H and 2-OEt-5-OHC₆H₃CO₂H

-   Adapt synthesis from U.S. Pat. No. 6,194,406 (Page 96) by using    propyl iodide and ethyl iodide.-   11. 4-OPr-3-OHC₆H₃CO₂H-   Adapt synthesis from WO 9626176-   12. 2-OPr-4-OHC₆H₃CO₂H-   Adapt synthesis from Takeda Kenkyusho Nempo (1965), 24,221-8 by    using propyl halide.-   13. 4-OEt-3-OHC₆H₃CO₂H-   Biomedical Mass Spectrometry (1985), 12(4), 163-9.-   14. 3-OPr-5-OHC₆H₃CO₂H-   Adapt synthesis from Taiwan Kexue (1996), 49(1), 51-56 by using    propyl halide.

The compound of formula XXI, where m is 0, R¹ is H and R³ is an alkylhaving 1 to 3 carbon atoms, i.e. compounds of formula:

are either commercially available or can be prepared according to themethods described in the literature as follows:

-   1. 5-Me-3-OHC₆H₃CO₂H and 2-Me-5-OHC₆H₃CO₂H-   WO 9619437.-   J.O.C. 2001, 66, 7883-88.-   2. 2-Me-4-OHC₆H₃CO₂H-   WO 8503701.-   3. 3-Et-2-OHC₆H₃CO₂H and 5-Et-2-OHC₆H₃CO₂H-   J. Med. Chem. (1971), 14(3), 265.-   4. 4-Et-2-OHC₆H₃CO₂H-   Yaoxue Xuebao (1998), 33(1), 67-71.-   5. 2-Et-6-OHC₆H₃CO₂H and 2-n-Pr-6-OHC₆H₃CO₂H-   J. Chem. Soc., Perkin Trans 1 (1979), (8), 2069-78.-   6. 2-Et-3-OHC₆H₃CO₂H-   JP 10087489 and WO 9628423.-   7. 4-Et-3-OHC₆H₃CO₂H-   J.O.C. 2001, 66, 7883-88.-   WO 9504046.-   8. 2-Et-5-OHC₆H₃CO₂H-   J.A.C.S (1974), 96(7), 2121-9.-   9. 2-Et-4-OHC₆H₃CO₂H and 3-Et-4-OHC₆H₃CO₂H-   JP 04282345.-   10. 3-n-Pr-2-OHC₆H₃CO₂H-   J.O.C (1991), 56(14), 4525-29.-   11. 4-n-Pr-2-OHC₆H₃CO₂H-   EP 279630.-   12. 5-n-Pr-2-OHC₆H₃CO₂H-   J. Med. Chem (1981), 24(10), 1245-49.-   13. 2-n-Pr-3-OHC₆H₃CO₂H-   WO 9509843 and WO 9628423.-   14. 4-n-Pr-3-OHC₆H₃CO₂H-   WO 9504046.-   15. 2-n-Pr-5-OHC₆H₃CO₂H-   Synthesis can be adapted from J.A.C.S (1974), 96(7), 2121-9 by using    ethyl alpha formylvalerate.-   16. 3-n-Pr-4-OHC₆H₃CO₂H-   Polymer (1991), 32(11) 2096-105.-   17. 2-n-Pr-4-OHC₆H₃CO₂H-   3-Propylphenol can be methylated to 3-Propylanisole, which was then    formylated to 4-Methoxy-3-benzaldehyde. The aldehyde can be oxidized    by Jone's reagent to give corresponding acid and deprotection of    methyl group by BBr₃ will give the title compound.-   18. 1. 3-Et-5-OHC₆H₃CO₂H and 3-Pr-n-5-OHC₆H₃CO₂H-   Adapt synthesis from J.O.C. 2001, 66, 7883-88 by using    2-Ethylacrolein and 2-Propylacrolein.    Use in Methods of Treatment

This invention provides a method for treating a mammalian subject with acondition selected from the group consisting of insulin resistancesyndrome and diabetes (both primary essential diabetes such as Type IDiabetes or Type II Diabetes and secondary nonessential diabetes),comprising administering to the subject an amount of a biologicallyactive agent as described herein effective to treat the condition. Inaccordance with the method of this invention a symptom of diabetes orthe chance of developing a symptom of diabetes, such as atherosclerosis,obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy,neuropathy, retinopathy, foot ulceration and cataracts, each suchsymptom being associated with diabetes, can be reduced. This inventionalso provides a method for treating hyperlipidemia comprisingadministering to the subject an amount of a biologically active agent asdescribed herein effective to treat the condition. As shown in theExamples, compounds reduce serum triglycerides and free fatty acids inhyperlipidemic animals. This invention also provides a method fortreating cachexia comprising administering to the subject an amount of abiologically active agent as described herein effective to treat thecachexia. This invention also provides a method for treating obesitycomprising administering to the subject an amount of a biologicallyactive agent as described herein effective to treat the condition. Thisinvention also provides a method for treating a condition selected fromatherosclerosis or arteriosclerosis comprising administering to thesubject an amount of a biologically active agent as described hereineffective to treat the condition. The active agents of this inventionare effective to treat hyperlipidemia, fatty liver disease, cachexia,obesity, atherosclerosis or arteriosclerosis whether or not the subjecthas diabetes or insulin resistance syndrome. The agent can beadministered by any conventional route of systemic administration.Preferably the agent is administered orally. Accordingly, it ispreferred for the medicament to be formulated for oral administration.Other routes of administration that can be used in accordance with thisinvention include rectally, parenterally, by injection (e.g.intravenous, subcutaneous, intramuscular or intraperitioneal injection),or nasally.

Further embodiments of each of the uses and methods of treatment of thisinvention comprise administering any one of the embodiments of thebiologically active agents described above. In the interest of avoidingunnecessary redundancy, each such agent and group of agents is not beingrepeated, but they are incorporated into this description of uses andmethods of treatment as if they were repeated.

Many of the diseases or disorders that are addressed by the compounds ofthe invention fall into two broad categories: Insulin resistancesyndromes and consequences of chronic hyperglycemia. Dysregulation offuel metabolism, especially insulin resistance, which can occur in theabsence of diabetes (persistent hyperglycemia) per se, is associatedwith a variety of symptoms, including hyperlipidemia, atherosclerosis,obesity, essential hypertension, fatty liver disease (NASH; nonalcoholicsteatohepatitis), and, especially in the context of cancer or systemicinflammatory disease, cachexia. Cachexia can also occur in the contextof Type I Diabetes or late-stage Type II Diabetes. By improving tissuefuel metabolism, active agents of the invention are useful forpreventing or amelioriating diseases and symptoms associated withinsulin resistance, as is demonstrated in animals in the Examples. Whilea cluster of signs and symptoms associated with insulin resistance maycoexist in an individual patient, it many cases only one symptom maydominate, due to individual differences in vulnerability of the manyphysiological systems affected by insulin resistance. Nonetheless, sinceinsulin resistance is a major contributor to many disease conditions,drugs which address this cellular and molecular defect are useful forprevention or amelioration of virtually any symptom in any organ systemthat may be due to, or exacerbated by, insulin resistance.

When insulin resistance and concurrent inadequate insulin production bypancreatic islets are sufficiently severe, chronic hyperglycemia occurs,defining the onset of Type II diabetes mellitus (NIDDM). In addition tothe metabolic disorders related to insulin resistance indicated above,disease symptoms secondary to hyperglycemia also occur in patients withNIDDM. These include nephropathy, peripheral neuropathy, retinopathy,microvascular disease, ulceration of the extremities, and consequencesof nonenzymatic glycosylation of proteins, e.g. damage to collagen andother connective tissues. Attenuation of hyperglycemia reduces the rateof onset and severity of these consequences of diabetes. Because, as isdemonstrated in the Examples, active agents and compositions of theinvention help to reduce hyperglycemia in diabetes, they are useful forprevention and amelioration of complications of chronic hyperglycemia.

Both human and non-human mammalian subjects can be treated in accordancewith the treatment method of this invention. The optimal dose of aparticular active agent of the invention for a particular subject can bedetermined in the clinical setting by a skilled clinician. In the caseof oral administration to a human for treatment of disorders related toinsulin resistance, diabetes, hyperlipidemia, fatty liver disease,cachexia or obesity the agent is generally administered in a daily doseof from 1 mg to 400 mg, administered once or twice per day. In the caseof oral administration to a mouse the agent is generally administered ina daily dose from 1 to 300 mg of the agent per kilogram of body weight.Active agents of the invention are used as monotherapy in diabetes orinsulin resistance syndrome, or in combination with one or more otherdrugs with utility in these types of diseases, e.g. insulin releasingagents, prandial insulin releasers, biguanides, or insulin itself. Suchadditional drugs are administered in accord with standard clinicalpractice. In some cases, agents of the invention will improve theefficacy of other classes of drugs, permitting lower (and therefore lesstoxic) doses of such agents to be administered to patients withsatisfactory therapeutic results. Established safe and effective doseranges in humans for representative compounds are: metformin 500 to 2550mg/day; glyburide 1.25 to 20 mg/day; GLUCOVANCE (combined formulation ofmetformin and glyburide) 1.25 to 20 mg/day glyburide and 250 to 2000mg/day metformin; atorvastatin 10 to 80 mg/day; lovastatin 10 to 80mg/day; pravastatin 10 to 40 mg/day; and simvastatin 5-80 mg/day;clofibrate 2000 mg/day; gemfibrozil 1200 to 2400 mg/day, rosiglitazone 4to 8 mg/day; pioglitazone 15 to 45 mg/day; acarbose 75-300 mg/day;repaglinide 0.5 to 16 mg/day.

Type I Diabetes Mellitus: A patient with Type I diabetes manages theirdisease primarily by self-administration of one to several doses ofinsulin per day, with frequent monitoring blood glucose to permitappropriate adjustment of the dose and timing of insulin administration.Chronic hyperglycemia leads to complications such as nephropathy,neuropathy, retinopathy, foot ulceration, and early mortality;hypoglycemia due to excessive insulin dosing can cause cognitivedysfunction or unconsciousness. A patient with Type I diabetes istreated with 1 to 400 mg/day of an active agent of this invention, intablet or capsule form either as a single or a divided dose. Theanticipated effect will be a reduction in the dose or frequency ofadministration of insulin required to maintain blood glucose in asatisfactory range, and a reduced incidence and severity of hypoglycemicepisodes. Clinical outcome is monitored by measurement of blood glucoseand glycosylated hemoglobin (an index of adequacy of glycemic controlintegrated over a period of several months), as well as by reducedincidence and severity of typical complications of diabetes. Abiologically active agent of this invention can be administered inconjunction with islet transplantation to help maintain theanti-diabetic efficacy of the islet transplant.

Type II Diabetes Mellitus: A typical patient with Type II diabetes(NIDDM) manages their disease by programs of diet and exercise as wellas by taking medications such as metformin, glyburide, repaglinide,rosiglitazone, or acarbose, all of which provide some improvement inglycemic control in some patients, but none of which are free of sideeffects or eventual treatment failure due to disease progression. Isletfailure occurs over time in patients with NIDDM, necessitating insulininjections in a large fraction of patients. It is anticipated that dailytreatment with an active agent of the invention (with or withoutadditional classes of antidiabetic medication) will improve glycemiccontrol, reduce the rate of islet failure, and reduce the incidence andseverity of typical symptoms of diabetes. In addition, active agents ofthe invention will reduce elevated serum triglycerides and fatty acids,thereby reducing the risk of cardiovascular disease, a major cause ofdeath of diabetic patients. As is the case for all other therapeuticagents for diabetes, dose optimization is done in individual patientsaccording to need, clinical effect, and susceptibility to side effects.

Hyperlipidemia: Elevated triglyceride and free fatty acid levels inblood affect a substantial fraction of the population and are animportant risk factor for atherosclerosis and myocardial infarction.Active agents of the invention are useful for reducing circulatingtriglycerides and free fatty acids in hyperlipidemic patients.Hyperlipidemic patients often also have elevated blood cholesterollevels, which also increase the risk of cardiovascular disease.Cholesterol-lowering drugs such as HMG-CoA reductase inhibitors(“statins”) can be administered to hyperlipidemic patients in additionto agents of the invention, optionally incorporated into the samepharmaceutical composition.

Fatty Liver Disease: A substantial fraction of the population isaffected by fatty liver disease, also known as nonalcoholicsteatohepatitis (NASH); NASH is often associated with obesity anddiabetes. Hepatic steatosis, the presence of droplets of triglycerideswith hepatocytes, predisposes the liver to chronic inflammation(detected in biopsy samples as infiltration of inflammatory leukocytes),which can lead to fibrosis and cirrhosis. Fatty liver disease isgenerally detected by observation of elevated serum levels ofliver-specific enzymes such as the transaminases ALT and AST, whichserve as indices of hepatocyte injury, as well as by presentation ofsymptoms which include fatigue and pain in the region of the liver,though definitive diagnosis often requires a biopsy. The anticipatedbenefit is a reduction in liver inflammation and fat content, resultingin attenuation, halting, or reversal of the progression of NASH towardfibrosis and cirrhosis.

Pharmaceutical Compositions

This invention provides a pharmaceutical composition comprising abiologically active agent as described herein and a pharmaceuticallyacceptable carrier. Further embodiments of the pharmaceuticalcomposition of this invention comprise any one of the embodiments of thebiologically active agents described above. In the interest of avoidingunnecessary redundancy, each such agent and group of agents is not beingrepeated, but they are incorporated into this description ofpharmaceutical compositions as if they were repeated.

Preferably the composition is adapted for oral administration, e.g. inthe form of a tablet, coated tablet, dragee, hard or soft gelatincapsule, solution, emulsion or suspension. In general the oralcomposition will comprise from 1 mg to 400 mg of such agent. It isconvenient for the subject to swallow one or two tablets, coatedtablets, dragees, or gelatin capsules per day. However the compositioncan also be adapted for administration by any other conventional meansof systemic administration including rectally, e.g. in the form ofsuppositories, parenterally, e.g. in the form of injection solutions, ornasally.

The biologically active compounds can be processed with pharmaceuticallyinert, inorganic or organic carriers for the production ofpharmaceutical compositions. Lactose, corn starch or derivativesthereof, talc, stearic acid or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragees and hardgelatin capsules. Suitable carriers for soft gelatin capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like. Depending on the nature of the active ingredient no carriersare, however, usually required in the case of soft gelatin capsules,other than the soft gelatin itself. Suitable carriers for the productionof solutions and syrups are, for example, water, polyols, glycerol,vegetable oils and the like. Suitable carriers for suppositories are,for example, natural or hardened oils, waxes, fats, semil-liquid orliquid polyols and the like.

The pharmaceutical compositions can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,coating agents or antioxidants. They can also contain still othertherapeutically valuable substances, particularly antidiabetic orhypolipidemic agents that act through mechanisms other than thoseunderlying the effects of the compounds of the invention. Agents whichcan advantageously be combined with compounds of the invention in asingle formulation include but are not limited to biguanides such asmetformin, insulin releasing agents such as the sulfonylurea insulinreleaser glyburide and other sulfonylurea insulin releasers,cholesterol-lowering drugs such as the “statin” HMG-CoA reductaseinhibitors such as atrovastatin, lovastatin, pravastatin andsimvastatin, PPAR-alpha agonists such as clofibrate and gemfibrozil,PPAR-gamma agonists such as thiazolidinediones (e.g. rosiglitazone andpioglitazone, alpha-glucosidase inhibitors such as acarbose (whichinhibit starch digestion), and prandial insulin releasers such asrepaglinide. The amounts of complementary agents combined with compoundsof the invention in single formulations are in accord with the dosesused in standard clinical practice. Established safe and effective doseranges for certain representative compounds are set forth above.

The invention will be better understood by reference to the followingexamples which illustrate but do not limit the invention describedherein.

CHEMICAL SYNTHESIS EXAMPLES Example 1

3-(2,6-Dimethylbenzyloxy)phenylacetic acid Step A: Preparation of Ethyl3-hydroxyphenylacetate

To a stirred solution of 3-Hydroxyphenylacetic acid (10 g, 65.7 mmol)and 1,3-dicyclohexylcarbodiimide (DCC, 16.27 g, 78.8 mmol) in DMF (30ml) was added pyridine (2.5 ml) followed by absolute ethanol (15 ml,255.5 mmol). The reaction mixture was stirred at room temperature for 16hours, filtered, concentrated and purified by flash chromatography on asilica gel column (hex: ethyl acetate 2:1) to give the title compound.

¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 3.5 (s, 2H); 4.1 (q, 2H); 6.6-7.2(m, 4H).

Step B: Preparation of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate

A solution of 2,6-Dimethylbenzyl alcohol (5.25 g, 38.6 mmol) anddiisopropyl azodicarboxylate (DIAD, 8.49 g, 42 mmol) in THF (30 ml) andDMF (13 ml) was added drop wise to a solution of Ethyl3-hydroxyphenylacetate (Step A, 6.66 g, 37 mmol) and triphenylphosphine(11 g, 42 mmol) in THF (100 ml). The reaction mixture was stirred atroom temperature for 4 hours, diluted with ether and washed with water.The organic layer was dried over Na₂SO₄, filtered, concentrated, andpurified by flash chromatography on a silica gel column (hex: ethylacetate 1:1) to give the title compound.

¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.4 (s, 6H); 3.5 (s, 2H); 4.1 (q,2H); 5.1 (s, 2H); 6.9 (m, 2H); 7.15-7.35 (m, 5H).

Step C: Preparation of 3-(2,6-Dimethylbenzyloxy)phenylacetic acid

To a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate(Step B, 4 g, 13.6 mmol) in absolute ethanol (30 ml) was added 1N NaOH(20 ml) at room temperature. The reaction mixture was stirred for 3hours, acidified by 1N HCl, and concentrated. The residue was taken intochloroform and washed with 1N HCl, dried over Na₂SO₄, filtered,concentrated and purified by flash chromatography on a silica gel column(hex:ethyl acetate 1:1) to give the title compound.

¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 3.65 (s, 2H); 5.1 (s, 2H); 6.9 (m,2H); 7.15-7.35 (m, 5H).

Example 2

3-(2,6-Dimethylbenzyloxy)benzoic acid Step A: Preparation of Ethyl3-(2,6-dimethylbenzyloxy)benzoate

To a stirred solution of Ethyl 3-hydroxybenzoate (12.21 g, 73.47 mmol)and triphenylphosphine (21.01 g, 80.13 mmol) in dry THF (100 ml) wasadded dropwise a solution of 2,6-Dimethylbenzyl alcohol (10 g, 73.5mmol) and diisopropyl azodicarboxylate (16.19 g, 80.13 mmol) in dry THF(35 ml) and dry DMF (15 ml) at ambient temperature. After three hours ofstirring at room temperature, the reaction mixture was diluted withdiethyl ether and washed twice with water and brine. The combinedorganic layer was dried over Na₂SO₄, filtered, concentrated and purifiedby flash chromatography using ethyl acetate:hexane (1:3) as elutent.

¹H NMR (270 MHz, CDCl₃): 1.4 (t, 3H); 2.4 (s, 6H); 4.4 (q, 2H); 5.1 (s,2H); 7.1 (m, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.9 (m, 2H).

Step B: Preparation of 3-(2,6-Dimethylbenzyloxy)benzoic acid

1N NaOH (86 ml) was added to a stirred solution of Ethyl3-(2,6-dimethylbenzyloxy)benzoate (Step A, 16.31 g, 57.4 mmol) inabsolute alcohol (150 ml). After 3 hours of stirring at roomtemperature, the reaction mixture was acidified with 1M HCl andconcentrated in vacuo. The organic residue was taken into chloroform andwashed with 1N HCl, dried over Na₂SO₄, filtered, concentrated andpurified by flash chromatography using chloroform:methanol (95:5 spikedwith acetic acid) as elutent.

¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 5.1 (s, 2H); 7.15-7.35 (m, 4H);7.4 (t, 1H); 7.8 (m, 2H).

Example 3 3-(2,6-Dimethylbenzyloxy)benzoic acid Step A: MitsunobuCoupling—Ethyl 3-(2,6-dimethylbenzyloxy)benzoate

TABLE 1

hydroxy Cpd ester TPP THF benzyl-OH DIAD THF product MW 166.17 262.29136.19 202.21 284.35 Mass 15.0 25.8 12.3 19.9 Vol 40 19.4 40 Mol 0.0900.098 0.090 0.098 D 1.027 Theoretical yield 25.7 g; actual yield 19.85g; fractional yield 0.773. Mass = g; vol = mL

A solution of ethyl 3-hydroxybenzoate and triphenylphosphine inanhydrous THF was cooled in an ice bath to 5° C. under nitrogen. In aseparate flask, a solution of 2,6-dimethylbenzyl alcohol and DIAD inanhydrous THF was prepared and transferred via cannula to first flask.The addition was very exothermic with a rise from 5° C. to 18° C. withinthe first 2 minutes of the addition (several mLs). The addition wascompleted over 22 min with a maximum temperature of 24° C. After 30 minof stirring, a precipitate formed and the ice bath was removed. Tlc(hexanes:ether 1:1, UV) after 2.5 h showed a trace of starting materialremained.

A variety of solvent systems were used in an attempt to better separateTPP from the product, they included: 10:3 hexanes:ether; 4:1hexanes:EtOAc; CH₂Cl₂; 1:1 CH₂Cl₂; hexanes 10% CH₂Cl₂ in hexanes; and 5%ether in hexanes. The last solvent system gave the best separation,solvents with CH₂Cl₂ in ti tended to elute the product and TPP togetherand quite fast.

TABLE 2 tlc data cpd Rf(H:E1:1) Rf(5% E/H) TPP 0.86 0.61 product 0.750.27 phenol 0.49 0 BnOH 0.41 0 TPP = O 0.06 0 H = hexanes E = ethylether

After 7 h, the reaction mixture was filtered to remove the solids (14.3g, tlc showed it was TPP oxide) and the filter cake was rinsed withhexanes: ether 1:1 (60 mL). The filtrate was concentrated to give ayellow mixture of oil and solids. This was taken up in 100 mL ether and100 mL hexanes and allowed to sit for ˜1 h. The solids were collected byvacuum filtration (24.0 g, tlc showed only TPP oxide, total solidsremoved was 38.3 g) and the filtrate was concentrated to give a creamcolored solid.

The solid was dissolved in 100 mL CH₂Cl₂ and applied to a pad of silicagel (9.5 cm diameter by 6 cm high, ˜325 g). This was eluted with CH₂Cl₂and collected into 2×500 mL and 2×250 mL flasks. The product and TPPcoeluted into the first 2 flasks and TPP oxide was retained.Concentrated the first 2 fractions to give 23.6 g of white powder. LC/MS(labeled M02130-01) showed 78% pure desired product with 11% TPP as themajor impurity.

The crude product was dissolved in ˜100 mL ether with heat and allowedto cool. A small amount of solid precipitated. Added 70 g silica gel andconcentrated. This was applied to a pad of silica gel (260 g, more thanequivalent to a Biotage 75S) and eluted with 1 L 5% ether in hexanes andcollected ˜200 mL fractions (4 fractions). The first fraction containedTPP and the 4th fraction was almost pure product, the second and thirdwere cross fractions. The silica gel was eluted with 1 L 30% ether inhexanes and collected into 3 fractions. Fractions 5 & 6 had product andwere concentrated to give a white solid, 19.85 g (77% yield).

¹H and ¹³C NMR spectra were consistent with the desired product.

LC/MS showed M+H=285.1 and 97.7% purity by UV at 250 nm.

¹H NMR (270 MHz, CDCl₃): 1.4 (t, 3H); 2.4 (s, 6H); 4.4 (q, 2H); 5.1 (s,2H); 7.1 (m, 2H); 7.2 (m, 2H); 7.4 (t, 1H); 7.7 (m, 2H).

Step B: Saponification

TABLE 3

cpd ester EtOH 40% NaOH water product MW 284.35 10 N 256.30 eq 2.13 mass10.0 vol 250 7.5 10 mol 0.035 0.075 Theoretical yield 9.01 g; actualyield 5.0 g; fractional yield 0.55

The ester (10 g) from Step A was taken up in 50 mL absolute EtOH. It wasnot very soluble and addition 50 mL portions of EtOH was added until 250mL was added. There were still some solids present and heat was appliedto form a solution (46° C.). A solution of 7.5 mL 10 N NaOH diluted with10 mL water was added and the solution was stirred for 1 h. Tlc(hexanes:ether, UV) showed the ester was consumed and an intense spotappeared on the baseline.

Work Up

The reaction was concentrated on a rotary evaporator at 50° C. give awhite solid. The solid was slurried in 250 mL deionized water and theinsoluble material was collected by filtration. The filtrate was setaside for the time being.

The filter cake was rinsed with 2×200 mL ether and examined by LC/MSafter each wash. The purity was 98.4% and 98.7% respectively. The solidswere stirred in 200 mL ether for 15 min and collected but filtration.LC/MS showed it was 99.5% pure. The solids were slurried in 100 mLdeionzed water and treated with 2.5 mL concentrated HCl. A check with pHpaper indicated pH1. The slurry was stirred for 22 min and collected byvacuum filtration. The filter cake was rinsed with several portions ofwater (˜100 mL total volume). Dried in vacuo at 45° C. with P₂O₅.

¹H NMR spectrum was consistent with the desired product, broad OHcentered at ˜6 ppm.

¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 5.1 (s, 2H); 7.1 (m, 2H); 7.15-7.3(m, 2H); 7.4 (t, 1H); 7.8 (m, 21).

Example 4 6-[3-(2,6-Dimethylbenzyloxy)-phenyl]-hexanoic acid

Step A: Synthesis of triphenylethylvalerate phosphonium bromide

TABLE 4

Compound MW Moles grams ml Density Triphenylphosphine 262.29 0.045011.80 Ethyl-5-bromovalerate 209.08 0.0600 12.54 9.46 1.321 Toluene 92.1325

Dissolved 11.80 g of triphenylphosphine in 25 ml of toluene undernitrogen in a 3-necked, 100 ml round bottom flask equipped with a stirbar, thermocouple and a reflux condenser with a nitrogen inlet. 12.54 gof ethyl-5-bromovalerate was added to the solution, heated to reflux(110° C.) and stirred for 2 hrs. The reaction was analyzed after 1 and 2hrs. The reaction was cooled to room temperature (<25° C.) and thetoluene was decanted away from the oily solid. The residue was slurriedin 100 ml of hexanes 3× decanting the hexanes each time. The oilyresidue was heated on a Kugelrohr apparatus at 40° C., 0.1 Torr for 30min. to afford 19.0 g (89.6%) of a white oily solid. NMR (³²P) and NMR(¹³C) showed the desired product.

Step B: Preparation of 6-[3-(2,6 dimethylbenzyloxy)-phenyl]-hex-5-enoicacid ethyl ester

TABLE 5

Compound MW Moles grams MI Triphenylethyvalerate 471.37 0.0282 13.29phosphonium bromide 3-(2,6-dimethylbenzyloxy) 240.30 0.0208 5.00benzaldehyde Sodium hydride 24.00 0.0310 0.745 Dimethyl sulfoxide 78.1340/20

A mixture of 13.29 g of triphenylethylvalerate phosphonium bromide and0.745 g of sodium hydride in 40 ml of DMSO was stirred for 30 min, undernitrogen in a 3-necked, 100 ml round bottom flask equipped with a stirbar, reflux condenser with a nitrogen inlet and a thermocouple. Themixture changed from light yellow to brown and heated to 40.2° C. from23.2° C. 5.00 g of 3-(2,6-dimethylbenzyloxy)benzaldehyde was dissolvedin 20 ml of DMSO and added, dropwise over a 4 min. period to thereaction mixture. The mixture heated to 26.8° C. from 21.8° C. Thereaction mixture was stirred and allowed to cool to room temperature.The reaction was analyzed after 1 hr. and LC-MS showed almost all thestarting aldehyde left and ˜3% desired product. The reaction mixture washeated to 50° C. and stirred for 3 hrs. The reaction was analyzed after2 and 3 hrs. LC-MS showed ˜20% starting aldehyde left and 17% desiredproduct. The reaction was cooled to room temperature and placed in arefrigerator overnight.

The reaction mixture was allowed to warm to room temperature andstirred. A mixture of 5.56 g (118 mM) of triphenylethylvaleratephosphonium bromide and 0.312 g of sodium hydride in 15.0 ml of DMSO wasstirred for 30 min. under nitrogen. The mixture was added, in bolus, tothe reaction, heated to 50° C. and stirred for 6 hrs.

¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 1.8 (m, 2H); 2.2-2.4 (m, 10H); 4.2(q, 2H); 5.1 (s, 2H); 5.6-6.2 (m, 1H); 6.4 (t, 1H); 6.9-7.3 (m, 7H).

Step C: Preparation of6-[3-(2,6-dimethylbenzyloxy)-phenyl]-ethylhexanoate

Reference: Journal of Org. Chemistry, Vol. 34, No. 11, p. 368-485.November 1969

TABLE 6

Compound MW mMoles grams ml 6-[3-(2,6-dimethylbenzyloxy)- 352.47 7.702.71 phenyl]-hex-enoic acid ethyl ester Tris(triphenylphosphine) 925.23.028 .0259 Chlororhodium (I) Benzene 78.11 60.0 Absolute ethanol 46.0760.02.71 g of 6-[3{2,6-dimethylbenzyloxy)-phenyl]-hex-5-enoic acid ethylester was dissolved in 120 ml of degassed 1:1 mixture of benzene andabsolute ethanol in a 300 ml stainless steel Parr pressure reactor.0.259 g of tris(triphenylphosphine)chlororhodium (I) (Wilkinson'scatalyst) was added to the solution. The reaction mixture was sparged 5×with hydrogen, heated to 60° C., 80 psi with hydrogen and stirredovernight.

The reaction was cooled to room temperature and vented. Analysis byLC-MS showed no starting olefin. The reaction solution was sparged withnitrogen and filtered through a bed of celite. The filtrate wasconcentrated in vacuo to afford 3.40 g of a brown oil. The oil wasdissolved in 12 ml of 1:1, hexanes: chloroform. The silica gel waseluted with 100 ml of 1:1, hexanes: chloroform and 200 ml of 95:5,hexanes:ethyl acetate collecting 50 ml fractions. Pure fractions werecombined and concentrated in vacuo to afford 2.70 g (99.0%) of a darkyellow oil. LC-MS showed the desired product ˜72%. The product was usedwithout further purification.

Step D: Preparation of 6-[3-(2,6-Dimethylbenzyloxy)-phenyl]-hexanoicacid

TABLE 7

Compound MW mMoles grams ml 6-[3-(2,6-dimethylbenzyloxy)- 354.48 0.00762.69 phenyl]ethythexanoate Ethanol 35 1.0N sodium hydroxide 40.0 10

2.69 g of 6-[3-(2,6-dimethylbenzyloxy)-phenyl]-ethylhexanoate wasdissolved in 35 ml of absolute ethanol and 10 ml of 1N aqueous sodiumhydroxide in a 100 ml round bottom flask equipped with a stir bar and areflux condenser. The yellow solution was heated to reflux and stirredfor 2 hrs. The reaction was analyzed and LC-MS showed no starting ethylester. The reaction was cooled to room temperature and concentrated invacuo to a yellow oil that mostly solidified on standing; 50 ml of waterwas added to the residue and stirred 10 min. The aqueous solution wasextracted 3× with 50 ml of ethyl acetate. The aqueous layer wasacidified with 3 ml of 6N aqueous HCl solution and extracted 3× with 50ml of ethyl acetate. The combined organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to afford ˜2.2 g of a gummyyellow solid. The residue was stirred in 75 ml of water for 30 min. Thesolids were collected by filtration and dried in a vacuum oven at 40° C.to afford 1.62 g (90.5%) of beige solid. LC-MS and NMR showed thedesired product >98%.

¹H NMR (270 MHz, CDCl₃): 1.4 (m, 2H); 1.7 (m, 4H); 2.3-2.4 (m, 8H); 2.6(t, 2H); 5.0 (s, 2H); 6.8 (m, 3H); 7.0-7.3 (m, 4H).

Example 5 5-[3-(2,6-Dimethylbenzyloxy)-phenyl]-pentanoic acid

Step A: Preparation of 5-[3-(2,6-dimethylbenzyloxy)-phenyl]-pent-4-enoicacid ethyl ester

TABLE 8

Compound MW Moles grams ml Triphenylethylbutyrate 457.34 0.0220 10.06phosphonium bromide 3-(2,6-dimethylbenzyloxy) 240.30 0.0162 3.89benzaldehyde Sodium hydride 24.00 0.0242 0.581 Dimethylsulfoxide 78.1330.0/15.0

A mixture of 10.06 g of triphenylethylbutyrate phosphonium bromide and0.581 g of sodium hydride in 30.0 ml of DMSO was stirred for 30 min.under nitrogen in a 3-necked, 100 ml round bottom flask equipped with astir bar, reflux condenser with a nitrogen inlet a thermocouple. Themixture changed from yellow to orange and heated to 26.7° C. from 19.8°C. 3.89 g of 3-(2,6-dimethylbenzyloxy)benzaldehyde was dissolved in 15.0ml of DMSO and added, dropwise, over a 3 min period of the reactionmixture. The mixture changed from orange to yellow and heated to 34.0°C. from 26.7° C. The reaction mixture was stirred and allowed to cool toroom temperature for 3 hrs. The reaction was analyzed after 1 and 3 hrs.LC showed the progress of the reaction from ˜15% to ˜13% startingaldehyde left. The reaction mixture was heated to 50° C. and stirred for2 hrs. The reaction was analyzed after 1 and 2 hrs. LC-MS showed littlechange from the previous samples with ˜12% starting aldehyde left. Thereaction mixture was cooled to room temperature and placed in arefrigerator overnight.

The reaction mixture was allowed to warm to room temperature andstirred. A mixture of 3.20 g (70 mM) of triphenylethylbutyratephosphonium bromide and 0.185 g of sodium hydride in 10.0 ml of DMSO wasstirred for 30 min. under nitrogen. The mixture was added, in bolus, tothe reaction and stirred at room temperature for 2 hrs.

The reaction was analyzed after 1 and 2 hrs. LC showed the progress ofthe reaction from ˜13% to ˜4% starting aldehyde left. The reactionmixture was heated to 50° C. and stirred for 2 hrs. The reaction wascooled to room temperature and poured over 50 g of ice with 50 ml ofwater. The aqueous mixture was extracted 3× with 125 ml of ethyl acetateand the combined organic layer was dried over sodium sulfate, filteredand concentrated in vacuo to afford 12.9 g of a brown oil. LC showed˜40% desired product.

The oil dissolved in 30 ml of 95:5, hexanes:ethyl acetate andchromatographed on a BIOTAGE 75S silica gel column using 5 liters of95:5, hexanes:ethyl acetate. The desired product eluted quickly,possibly due to residual DMSO from the work up. The fractions containingthe desired product were combined and concentrated in vacuo to afford4.9 g of a yellow oil. The oil was dissolved in 10 ml of 1:1, hexanes:chloroform and placed on 30 g silica gel equilibrated with 1:1, hexanes:chloroform. The silica gel was eluted with 200 ml 1:1, hexanes:chloroform and 200 m11 of 9:1, hexanes:ethyl acetate collecting 50 mlfractions. Pure fractions were combined and concentrated in vacuo toafford 3.40 g (62.0%) of a faint yellow oil that mostly solidified uponstanding. LC-MS and NMR show the desired product >98% with about a 30:70cis to trans isomeric ratio based on the Wittig reaction producingpredominantly the trans isomer.

¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.4-2.7 (m, 10H); 4.1 (q, 2H); 5.1(s, 2H); 5.6-6.2 (m, 1H); 6.5 (t, 1H); 6.8 (m, 7H).

Step B: Preparation of5-[3-(2,6-dimethylbenzyloxy)-phenyl]-ethylpentanoate

Reference: The Journal of Org. Chemistry, Vol. 34, No. 11, p. 3684-85,November 1996

TABLE 9

Compound MW mMoles grams ml 5-[3-(2,6-dimethylbenzyloxy)- 338.4 6.802.30 phenyl]-pent-4-enoic acid ethyl ester Tris(triphenylphosphine)925.23 0.24 0.222 Chlororhodium (I) Benzene 78.11 55.0 Absolute ethanol46.07 55.0

2.50 g of 5-[3-(2,6-dimethylbenzyloxy)-phenyl]-pent-4-enoic and acidethyl ester was dissolved in 110 ml of a degassed 1:1 mixture of benzeneand absolute ethanol in a 300 ml stainless steel Parr pressure reactor.0.222 g of tris(triphenylphosphine)chlororhodium (I) (Wilkinson'scatalyst) was added to the solution. The reaction mixture was sparged 5×with hydrogen, heated to 60° C., 80 psi with hydrogen and stirredovernight.

The reaction was cooled to room temperature and vented. Analysis byLC-MS showed no starting olefin. The reaction solution was sparged withnitrogen and filtered through a bed of celite. The filtrate wasconcentrated in vacuo to afford 3.20 g of a brown oil. The oil wasdissolved in 12 ml of 1:1, hexanes: chloroform and placed on 30 g ofsilica gel equilibrated with 1:1, hexanes: chloroform. The silica getwas eluted with 100 ml of 1:1, hexanes: chloroform and 200 ml of 95:5,hexanes:ethyl acetate collecting 50 ml fractions. Pure fractions werecombined and concentrated in vacuo to afford 2.30 g (99.0%) of a faintyellow oil. LC-MS showed the desired product ˜93%. The product was usedwithout further purification.

¹H NMR (270 MHz, CDCl₃): 1 (t, 3H); 1.4 (m, 4H); 2.0 (t, 2H); 2.1 (s,6H); 2.4 (m, 2H); 3.8 (q, 2H); 4.7 (s, 2H); 6.5 (m, 3H); 6.8-7.0 (m,4H).

Step C: Preparation of 5-[3-(2,6-dimethylbenzyloxy)-phenyl]-pentanoicacid

TABLE 10

Compound MW moles grams ml 5-[3-(2,6-dimethylbenzyloxy)- 340.46 0.00802.72 phenyl]-ethylpentanoate Ethanol 35 1.0N sodium hydroxide 40.0 10

2.72 g of 5-[3-(2,6-dimethylbenzyloxy)-phenyl]-ethylpentanoate wasdissolved in 35 ml of absolute ethanol and 10 ml of 1N aqueous sodiumhydroxide in a 100 ml round bottom flask equipped with a stir bar and areflux condenser. The light yellow solution turned was heated to refluxand stirred for 1 hr. The reaction was analyzed and LC-MS showed nostarting ethyl ester. The reaction was cooled to room temperature andconcentrated in vacuo to a white solid. 50 ml of water was added todissolve the solid. The aqueous solution was extracted 3× with 50 ml ofethyl acetate. The aqueous layer was acidified with 3 ml of 6N aqueousHCl solution and extracted 3× with 50 ml of ethyl acetate. The combinedorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo to afford ˜2.5 g of a white gummy solid. The solid was stirredin 25 ml of hexanes for 30 min., collected by filtration and dried in avacuum oven at 40° C. to afford 2.12 g (84.8%) of a white solid. LC-MSand NMR showed the desired product >99%.

¹H NMR (270 MHz, CDCl₃): 1.7 (m, 4H); 2.4 (m, 8H); 2.6 (m, 2H); 5.0 (s,2H); 6.8 (m, 3H); 7.0-7.3 (m, 4H).

Example 6 3-[3-(2,6-dimethylbenzyloxy)-phenyl]-propionic acid

Step A: Synthesis of ethyl-3-hydroxyphenylpropionate

TABLE 11

Compound MW moles grams ml 3-(3-hydroxyphenyl)- 166.18 0.0301 5.00propionic acid Ethanol 46.07 5.0 Concentrated Sulfuric 96.03 0.5 acid

5.00 g 3-(3-hydroxyphenyl)propionic acid were dissolved in 50 ml ofabsolute ethanol in a 3-necked, 100 ml round bottom flask equipped witha mechanical stirrer, a reflux condenser and a thermocouple. 0.5 ml ofconcentrated sulfuric acid were added to the solution and heated toreflux (80° C.) and stirred for 2 hrs. The reaction was analyzed andLC-MS showed the desired product with no starting material. The reactionwas cooled to <5° C. in an ice bath and neutralized to pH ˜7 with 10 mlof 10% aqueous sodium carbonate solution. The neutralized solution wasconcentrated in vacuo to ˜10 ml and diluted with 25 ml of water. Thesolution was extracted 3× with 25 ml of ethyl acetate. The combineorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo to afford 5.06 g (86.5%) of a dark amber oil. LC-MS and NMR MFGshowed the desired product >99.5%.

¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.6 (t, 2H); 2.8 (t, 2H); 4.2 (q,2H); 6.7-6.8 (m, 3H); 7.2 (m, 1H).

Step B: Synthesis of ethyl-3-(2,6-dimethylbenzyloxy)phenylpropionate

TABLE 12

Compound MW moles grams ml Ethyl-3-hydroxyphenyl- 194.23 0.0260 5.05propionate 2,6-dimethylbenzyl alcohol 136.19 0.0271 3.69 Isopropylazodicarboxylate 202.21 0.0296 5.99 Triphenylphosphine 262.29 0.02967.76 Tetrahydofuran 72.11 24/76

A solution of 3.69 g of 2,6-dimethylbenzyl alcohol and 5.99 g ofdiisopropyl azodicarboxylate in 24 ml of THF was added, dropwise, to asolution of 5.05 g of ethyl-3-hydroxyphenylpropionate and 7.76 g oftriphenylphosphine in 76 ml of THF at such a rate as to keep thereaction temperature <25° C., (Tmax=22.3° C.). The reaction was stirredat room temperature for 4 hrs. in a 3-necked, 250 ml round bottom flaskequipped with a stir bar, addition funnel and thermocouple. The reactionwas analyzed after 3 and 4 hrs. at room temperature. LC-MS showed mostlydesired product with ˜4.5% starting material. The reaction wasconcentrated in vacuo to afford a dark yellow oil. 200 ml hexanes wasadded to the oil and the solution was stirred in an ice bath (<5° C.)for 1 hr. The solids were collected by filtration and washed 3× with 40ml of hexanes. The solids were analyzed and NMR showed that they are amixture of triphenylphosphine oxide and reduced DIAD. LC-MS showed thehexanes filtrate to contain ˜58% desired product. The filtrate wasconcentrated in vacuo to afford 10.2 g of a yellow oil. The oil wasdissolved in 5 ml of absolute ethanol 75 ml of hexanes was added and thesolution was placed in a freezer overnight. The solids were collected byfiltration and dried. NMR showed that 4.3 g of white solids to be ˜80%.The solids were combined with the hexanes/ethanol filtrate andconcentrated in vacuo to afford 9.3 g of a light yellow oil that wassaponified without further purification.

¹H NMR (270 MHz, CDCl₃): 1.2 (t, 3H); 2.4 (s, 6H); 2.6 (t, 2H); 3.0 (t,2H); 4.2 (q, 2H); 5.1 (s, 2H); 6.8 km, 3H); 7.2-7.4 (m, 4H).

Step C: Synthesis of 3-(2,6-dimethylbenzyloxy)phenylpropionic acid

TABLE 13

Compound MW moles grams ml Ethyl-3-(2,6-dimethylbenzyloxy) 312.40 9.3phenylpropionate Ethanol 46.07 75 7.5N sodium hydroxide 40.0 4.0

9.3 g of an oil containing ˜60%ethyl-3-(2,6-dimethylbenzyloxy)phenylpropionate was dissolved in 75 mlof absolute ethanol in a single necked, 250 ml round bottom flaskequipped with a stir bar and reflux condenser. 4.0 ml of 7.5N sodiumhydroxide was added to the solution. The light yellow solution washeated to reflux (80° C.) and stirred for 1 hr. The reaction wasanalyzed and LC-MS showed the desired product and no starting ester. Thereaction was cooled to room temperature and concentrated in vacuo toafford a yellow oil. The oil was dissolved in 25 ml of water andextracted 3× with 25 ml of ether. The aqueous layer was cooled to <5° C.in an ice bath and acidified to a pH=1 by slowly adding 15 ml of 6Naqueous HCl solution. The precipitated solid were collected byfiltration, washed 3× with 25 ml of water and air-dried. The solids wereslurried in 100 ml of hexanes and collect by filtration, washed 3× with25 ml of hexanes and air-dried. LC-MS showed the solids to be ˜80%desired product. The solids were heated to 70° C. in 44 ml of 3:1,absolute ethanol: water mixture. The solution was stirred and allowed tocool to room temperature in a tap water bath. The solids were collectedby filtration, washed with 20 ml of 3:1, absolute ethanol: water mixtureand air-dried. LC-MS showed the solid to be ˜98.5% desired product. Thesolids were heated to 70° C. in 36 ml of 3:1, absolute ethanol: watermixture. The solution was stirred and allowed to cool to roomtemperature in a tap water bath. The solids were collected byfiltration, washed with 20 ml of a 3:1, absolute ethanol: water mixtureand air-dried. LC-MS and NMR showed the solids to be >99.5% desiredproduct. The white solid was dried in a vacuum oven at 40° C. for 2 hrs.to afford 3.91 g (52.9%).

¹H NMR (270 MHz, CDCl₃): 2.4 (s, 6H); 2.2 (m, 2H); 3.0 (m, 2H); 5.1 (s,2H); 6.8 (m, 3H); 7.1-7.3 (m, 4H).

BIOLOGICAL ACTIVITY EXAMPLES

For all of the biological activity examples that follow, Compound CF wasproduced in accordance with chemical synthesis example 1. For the invivo activity experiments Compound CG was produced in accordance withsynthesis example 3. For the in vitro activity experiments Compound CGwas produced in accordance with synthesis example 2.

Example A Antidiabetic Effects in ob/ob Mice

Obese (ob/ob) mice have a defect in the protein leptin, a regulator ofappetite and fuel metabolism, leading to hyperphagia, obesity anddiabetes.

Male obese (ob/ob homozygote) C57BL/6J mice, approximately 8 weeks ofage, were obtained from Jackson Labs (Bar Harbor, Me.) and randomlyassigned into groups of 5 animals each such that the body weights (45-50g) and serum glucose levels (≧300 mg/dl in fed state) were similarbetween groups. A minimum of 7 days was allowed for adaptation afterarrival. All animals were maintained under controlled temperature (23°C.), relative humidity (50±5%) and light (7:00-19:00), and allowed freeaccess to standard chow (Formulab Diet 5020 Quality Lab Products,Elkridge, Md.) and water.

Treatment cohorts were given daily oral doses of vehicle (1%hydroxypropylmethylcellulose), Compounds BI, CF, CA, CB, CC, or CD for 2weeks. At the end of the treatment period 100 μl of venous blood waswithdrawn in a heparinized capillary tube from the retro-orbital sinusof ob/ob mice for serum chemistry analysis.

After 2 weeks of daily oral dosing, Compound BI (100 mg/kg) and CompoundCF (60 mg/kg) elicited a significant reduction in blood glucose (Table14), triglycerides and free fatty acids (Table 15) as described below.

TABLE 14 Effects of Compounds BI, CF, CA, CB, CC, and CD in the maleob/ob mouse model of Type II diabetes Groups Glucose mg/dL Glucose (% ofControl) Vehicle (Control) 423.6 ± 55.0 100.0 ± 13.0 BI - 30 mg/kg 301.4± 29.0 71.0 ± 7.0 BI - 60 mg/kg 248.8 ± 20.0  59.0 ± 5.0* BI - 100 mg/kg196.3 ± 6.0   46.0 ± 1.0* CF - 60 mg/kg 161.2 ± 14.0  38.0 ± 3.0* CA -60 mg/kg 402.6 ± 61.0   95 ± 14.0 CB - 60 mg/kg 494.4 ± 72.3 117.0 ±17.0 CC - 60 mg/kg 444.4 ± 89.5 105.0 ± 21.0 CD - 60 mg/kg 505.6 ± 63.5119.0 ± 15.0 *p < 0.05 significantly different compared withvehicle-control

TABLE 15 Effects of Compounds BI, CF, CA, CB, CC, and CD on plasma serumglucose, triglycerides, and free fatty acids in obese (ob/ob) miceGlucose ± Triglycerides ± Free Fatty Group SEM SEM Acids ± SEM Vehicle423.6 ± 55.0 121.8 ± 29.4  1612.4 ± 169.7 BI - 30 mg/kg 301.4 ± 29.066.6 ± 3.6 1272.8 ± 32.5 BI - 60 mg/kg 248.8 ± 20.0 61.4 ± 3.6 1168.6 ±56.7 BI - 100 mg/kg 196.3 ± 6.0  55.0 ± 3.4 1245.4 ± 20.0 BI - 60 mg/kg161.2 ± 14.0 53.8 ± 1.5 1081.6 ± 47.7 CA - 60 mg/kg 402.6 ± 61.0  92.6 ±13.7  1572.2 ± 118.0 CB - 60 mg/kg 494.4 ± 72.3 118.8 ± 18.0  2076.2 ±169.0 CC - 60 mg/kg 444.4 ± 89.5  91.6 ± 13.4  2043.6 ± 285.0 CD - 60mg/kg 505.6 ± 63.5 119.0 ± 14.2  1961.8 ± 194.2

Example B Antidiabetic Effects in db/db Mice

db/db mice have a defect in leptin signaling, leading to hyperphagia,obesity and diabetes. Moreover, unlike ob/ob mice on a C57BL/6Jbackground, db/db mice on a C57BL/KS background undergo failure of theirinsulin-producing pancreatic islet cells, resulting in progression fromhyperinsulinemia (associated with peripheral insulin resistance) tohypoinsulinemic diabetes.

Male obese (db/db homozygote) C57BL/Ksola mice approximately 8 weeks ofage, were obtained from Jackson Labs (Bar Harbor, Me.) and randomlyassigned into groups of 5-7 animals such that the body weights (50-55 g)and serum glucose levels (≧300 mg/dl in fed state) were similar betweengroups; male lean (db/+heterozygote) mice served as cohort controls. Aminimum of 7 days was allowed for adaptation after arrival. All animalswere maintained under controlled temperature (23° C.), relative humidity(50±5%) and light (7:00-19:00), and allowed free access to standard chow(Formulab Diet 5008, Quality Lab Products, Elkridge, Md.) and water.

Treatment cohorts were given daily oral doses of Vehicle (1%hydroxypropylmethylcellulose), Compounds BI, CE, BT, BV, BV orFenofibrate for 2 weeks. At the end of the treatment period 100 μl ofvenous blood was withdrawn in a heparinized capillary tube from theretro-orbital sinus of db/db mice for serum chemistry analysis.

Effects of compounds of the invention on nonfasting blood glucose areshown in Table 16; effects on serum triglycerides and free fatty acidsare shown in Table 17.

TABLE 16 The effects of Compounds BI, CE, BT, BU, BV and fenofibrate indb/db mice Groups Glucose mg/dL Glucose (% of Control) Vehicle (Control)692.5 ± 55.4 100 ± 8  BI - 100 mg/kg  347.0 ± 43.1*  50 ± 6* CE - 93mg/kg  372.0 ± 53.8*  54 ± 8* BT - 107 mg/kg 684.3 ± 63.6 99 ± 9 BU -128 mg/kg 533.3 ± 46.7 77 ± 7 BV - 115 mg/kg 789.5 ± 38.9 114 ± 6 Fenofibrate - 113 mg/kg 563.2 ± 49.0 81 ± 7 Blood glucose levels inlean, nondiabetic db/+ heterozygote mice were 208.5 ± 6.6 mg/dL

TABLE 17 Effect of Compounds BI, CE, BT, BU, BV and Fenofibrate on serumtriglycerides and free fatty acids in db/db mice Triglycerides ± SEMFree Fatty Acids ± SEM Group (mg/dL (μM) Lean 114.2 ± 8.7  2315.8 ±238.3 Vehicle 232.8 ± 20.7 3511.8 ± 257.6 BI 77.8 ± 5.3 1997.2 ± 196.4CE 132.0 ± 15.2 2867.4 ± 267.7 BT 211.5 ± 21.5 3897.7 ± 291.3 BU 172.5 ±9.9  3587.0 ± 156.3 BV 153.2 ± 14.2 3373.8 ± 233.6 Fenofibrate 109.3 ±9.1  3318.5 ± 208.7

Example C Antidiabetic Effects in db/db Mice

C57BU/Ksola (db/db) mice have a defect in leptin signaling, leading tohyperphagia, obesity and diabetes. Moreover, unlike ob/ob mice on aC57BL/6J background, db/db mice on a C57BLKS background undergo failureof their insulin-producing pancreatic islet cells, resulting inprogression from hyperinsulinemia (associated with peripheral insulinresistance) to hypoinsulinemic diabetes.

Male obese (db/db homozygote) C57BL/Ksola mice approximately 8 weeks ofage, were obtained from Jackson Labs (Bar Harbor, Me.) and sorted intogroups of 7 animals each animals such that the body weights (40-45 g)and serum glucose levels (≧300 mg/dl in fed state) were similar betweengroups. A minimum of 7 days was allowed for adaptation after arrival.All animals were maintained under controlled temperature (23° C.),relative humidity (50±5%) and light (7:00-19:00), and allowed freeaccess to standard chow (Formulab Diet 5008, Quality Lab Products,Elkridge, Md.) and water.

Treatment cohorts were given daily oral doses of vehicle (1%hydroxypropylmethylcellulose), Compounds BI, CF, CG, or phenylacetatefor 17 days. At the end of the treatment period, blood samples werecollected and serum glucose and triglycerides were measured. Astatistically significant reduction in blood glucose or triglyceridesversus animals treated with oral vehicle is considered a positivescreening result for a drug.

TABLE 18 The effects of Compounds BI, CF, CG, and phenylacetate in adb/db mouse model of type I diabetes Glucose mg/dL Triglycerides Groups(±SEM) (mg/dL) Vehicle (Control) 812 ± 34 352 ± 27 BI - 100 mg/kg 472 ±54 116 ± 4  BI - 150 mg/kg 348 ± 67 90 ± 6 CF - 30 mg/kg 586 ± 31 156 ±20 CF - 60 mg/kg 604 ± 36 120 ± 13 CF - 100 mg/kg 391 ± 61 92 ± 6 CG -100 mg/kg 753 ± 24 166 ± 14 Phenylacetate - 300 mg/kg 661 ± 64 171 ± 33*p < 0.05 significantly different compared with vehicle-control

Example D Transcription Activation Potential of Compounds on Human andMouse PPARα and PPARγ

Materials and Methods:

Cells were seeded in 24 well plates the day prior to transfection at5×10⁴-2×10⁵ cells/well, depending upon cell type. Cells were transfectedusing Lipofectamine 2000 reagent from Invitrogen. A total of 0.8 μgDNA/well was added to 50 μL of Optimem Reduced Serum media (serum free;Gibco). Lipofectamine 2000 was added (2.5 μL/well) to another tubecontaining 50 μL of Optimem media. Plasmid DNA was added at a ratio of4:3 (reporter:activator); where appropriate, salmon sperm DNA wassubstituted for activator expressing plasmid. The reporter plasmid usedwas pFR-Luc, which has the firefly luciferase gene under the control ofa GAL4 UAS (STRATAGENE) containing promoter. The activator expressingplasmids contain yeast GAL4 DNA binding domain (dbd) fusion of eitherhuman PPARα ligand binding domain (LBD; a.a. 167-468) or human PPARγ LBD(a.a. 176-479). DNA constructs containing the mouse PPARα or PPARγ LBDfused to the GAL4 DNA binding domain were also used. The two solutionswere incubated at room temperature for 5 min, and then combined. Thecombined solution was incubated at room temperature for approximately 30min. Cells were washed once with PBS, and 100 μL of transfection mixadded to each well. Plates were incubated at 37° C. in a 5% CO₂incubator for 4.5 hr, followed by aspiration of the transfection mix,with plates refed using EMEM complete media (supplemented with 10% FBS,1× glutamine). 24 hr post-transfection, plates were treated with theappropriate compounds in EMEM complete media, followed by washing oncewith PBS and addition of 100 μL 1× reporter lysis buffer/well (Promega)24 hr after treatment. Plates went through one freeze/thaw cycle priorto analysis. Approximately 10 μL of lysate was added to 100 μL offirefly luciferase substrate, mixed by pipetting, and analyzed on aluminometer for 10 s using the integration function (relative luciferaseunits/RLU) or on a Microbeta Trilux (luciferase counts per second/LCPS).Each treatment was performed in triplicate, and in multiple, separateexperiments.

Results:

TABLE 19 Mouse PPARγ LBD fusion protein: transcription activationpotential in Hepa1.6 cells (mouse hepatoma cell line). Values are inrelative luciferase units (RLU) ± standard deviation. controls BI CF Notreatment 208 ± 38 Na na 3 μM rosi 1817 ± 331 Na na 1 μM na 210 ± 51 361 ± 138 3 μM na 256 ± 33  602 ± 144 5 μM na 254 ± 81 710 ± 87 7 μM na265 ± 61  786 ± 418 10 μM  na 355 ± 53 1140 ± 111 30 μM  na  441 ± 2031253 ± 554 100 μM  na  820 ± 353 1534 ± 608 na = not applicable; nd =not done

TABLE 20a AND 20b Mouse PPARα and PPARγ LBD fusion proteins:transcription activation potential in C3A cells (human hepatoma cellline). Values are in luciferase counts per second (LCPS) ± standarddeviation. 20a. Mouse PPARα. Wy/control BI CE CF CG Reporter 8.73 ± 1.85na na na na No treatment 20.27 ± 2.61  na na na na  1 μM 406.73 ± 80.11 14.67 ± 11.08 9.47 ± 2.14 13.17 ± 7.84 4.43 ± 2.25  3 μM 295.8 ± 40.3115.2 ± 2.78 9.57 ± 2.61  5.63 ± 0.42 9.17 ± 3.72  10 μM 324.37 ± 11.06 15.1 ± 3.78 1.17 ± 2.49 153.15 ± 24.4  7.87 ± 0.7   30 μM   414 ± 122.5210.43 ± 1.81   7.4 ± 0.23 358.6 ± 5.23 11.63 ± 5.01  100 μM 325.3 ±91.83 15.37 ± 6.21  6.13 ± 0.17  201.5 ± 50.84 11.8 ± 8.95 200 μM 115.2± 21.52  18.6 ± 11.66   8 ± 1.88 106.77 ± 32.53 80.3 ± 2   20b. MousePPARγ. Rosiglitazone BI CE CF CG Reporter 8.73 ± 1.85 na na na na Notreatment 8.03 ± 1.82 na na na na  1 μM 196.8 ± 138.9 2.4 ± 2.26 14.3 ±4.5 0.33 ± 0.21 8.47 ± 5.01  3 μM  60.1 ± 29.14 2.6 ± 1.41 13.43 ± 8.5 10.6 ± 8.74 14.8 ± 4.3   10 μM 432.7 ± 137.4 2.2 ± 1.57  6.03 ± 3.7517.2 ± 21   20.87 ± 4.1   30 μM   378 ± 274.5 4.9 ± 4.42  9.6 ± 5.4688.2 ± 33.2 55.4 ± 30.6 100 μM 308.6 ± 110.1 2.63 ± 1.96   11.7 ± 11.745.8 ± 36.9 78.8 ± 23.1 200 μM Nd 65.77 ± 10.55  10.5 ± 9.2 93.6 ± 29.7101.2 ± 59.1  na = not applicable; nd = not done

Note: The concentrations listed in the preceding table are for the testcompounds. The concentration of rosiglitazone was one-fifth the testcompound concentration; thus 1 μM test compound was compared against 0.2μM rosiglitzaone, etc.

TABLE 21 Mouse PPARα and PPARγ LBD fusion proteins: transcriptionactivation potential in C3A cells. Values are in RLU ± standarddeviation. 21a. Mouse PPARα. controls CF CG Reporter only 2259 ± 300 nana No treatment 1217 ± 161 na na 100 μM Wy 55972 ± 5162 na na 100 μMfenoprofen 4440 ± 213 na na 100 μM BI 4421 ± 118 na na  1 μM Na 2694 ±159 361 ± 398  3 μM Na 4527 ± 740 706 ± 399  5 μM Na  7188 ± 1753 492 ±160  7 μM Na 14325 ± 1032 652 ± 190  10 μM Na 16680 ± 2432 394 ± 84   30μM Na 38105 ± 3133 651 ± 643 100 μM Na 41037 ± 5401  926 ± 1362 21b.Mouse PPARγ. controls BI CF CG No treatment  302 ± 119 na na na 3 μMrosi 17264 ± 8260 na na na 1 μM na 746 ± 362 146 ± 119 634 ± 195 3 μM na174 ± 153 579 ± 557 nd 5 μM na 996 ± 855 476 ± 527 nd 7 μM na 220 ± 137834 ± 984 nd 10 μM  na 479 ± 353 207 ± 107 405 ± 318 30 μM  na 557 ± 639 818 ± 1201 1562 ± 354  100 μM  na 3330 ± 1848 237 ± 216 2555 ± 1609 na= not applicable; nd = not done

TABLE 22 Human PPARα and PPARγ LBD fusion proteins: transcriptionactivation potential in C3A cells. Values are in LCPS ± standarddeviation. 22a. Human PPARα. Wy BI CF CE CG Reporter 21.93 ± 6.0  na nana na No treatment 180.8 ± 32.2 na na na na  1 μM 181.8 ± 47.6 127.7 ±7.1  37 ± 11.5  14.7 ± 14.6  10.9 ± 11.6  3 μM 153.1 ± 2.8   128 ± 70.747 ± 22.8 13.2 ± 5.8 19.1 ± 6.1  10 μM 315.4 ± 36.5 52.7 ± 8.2  19.9 ±7.8   26.2 ± 1.4 17.9 ± 5.2  30 μM 648.6 ± 47.5 55.4 ± 16.2 40.2 ±18.9   10.67 ± 1.2   38.2 ± 21.1 100 μM 412.23 ± 11.4  20.9 ± 13.1 19 ±14.2 6.33 ± 2.6 23.9 ± 5.3 200 μM nd 31.1 ± 29.4 12.9 ± 8.3   12.8 ± 3.7159.4 ± 29.6 22b. Human PPARγ. Rosiglitazone BI CE CF CG Reporter 21.9 ±6.1  na na na na No treatment 39.9 ± 17.5 na na na na  1 μM  124 ± 33.843.3 ± 11.6   60 ± 11.6  6.2 ± 0.6 47.9 ± 7.2  3 μM 134.8 ± 47.8   26 ±4.5 73.3 ± 30.9 49.4 ± 7.8  73.6 ± 39.1  10 μM 626.6 ± 227   40.1 ± 13.557.3 ± 22.6 141.5 ± 25.9  72.5 ± 28.2  30 μM 887.2 ± 338.2 22.9 ± 10.328.5 ± 16.4 230.4 ± 97.2 205.6 ± 37.1 100 μM 1034.1 ± 400.5  34.6 ± 15.637.7 ± 23.4 225.2 ± 57.5 403.6 ± 86.1 200 μM Nd 227.3 ± 25.8  12.3 ±4.8  280.1 ± 89.7  598.1 ± 190.4 na = not applicable; nd = not doneNote: The concentrations listed in the preceding table are for the testcompounds. The concentration of rosiglitazone was one-fifth the testcompound concentration; thus 1 μM test compound was compared against 0.2μM rosiglitzaone, etc.

1. A pharmaceutical composition adapted for oral administration,comprising a pharmaceutically acceptable carrier and from one milligramto four hundred milligrams of a biologically active agent, wherein theagent is a compound of the formula:

wherein n is 1 or 2; m is 1, 2, 4, or 5; q is 0 or 1; t is 0 or 1; R² isalkyl having from 1 to 3 carbon atoms; R³ is hydrogen, halo, alkylhaving from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbonatoms; A is 2,6-dimethylphenyl; or cycloalkyl having from 3 to 6 ringcarbon atoms wherein the cycloalkyl is unsubstituted or one or two ringcarbons are independently mono-substituted by methyl or ethyl; and R¹ ishydrogen or alkyl having 1 or 2 carbon atoms; or when R¹ is hydrogen, apharmaceutically acceptable salt of the compound.
 2. The pharmaceuticalcomposition of claim 1, wherein n is 1; q is 0; t is 0; R³ is hydrogen;and A is 2,6-dimethylphenyl.
 3. The pharmaceutical composition of claim1 in oral dosage form.
 4. The pharmaceutical composition of claim 2,wherein the biologically active agent is selected from the groupconsisting of: 3-(2,6-Dimethylbenzyloxy)phenylacetic acid;6-[3-(2,6-Dimethylbenzyloxy)-phenyl]-hexanoic acid; Ethyl6-[3-(2,6-dimethylbenzyloxy)-phenyl]-hexanoate;5-[3-(2,6-Dimethylbenzyloxy)-phenyl]-pentanoic acid; Ethyl5-[3-(2,6-dimethylbenzyloxy)-phenyl]-pentanoate;3-[3-(2,6-dimethylbenzyloxy)phenyl]-propionic acid; and Ethyl3-[3-(2,6-dimethylbenzyloxy)phenyl]-propanoate.
 5. The pharmaceuticalcomposition of claim 4, wherein the biologically active agent is3-(2,6-Dimethylbenzyloxy)-phenylacetic acid.
 6. A biologically activeagent, wherein the agent is a compound of the formula:

wherein n is 1 or 2; m is 1, 2, 4, or 5; q is 0 or 1; t is 0 or 1; R² isalkyl having from 1 to 3 carbon atoms; R³ is hydrogen, halo, alkylhaving from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbonatoms; A is 2,6-dimethylphenyl; and R¹ is hydrogen or alkyl having 1 or2 carbon atoms; or when R¹ is hydrogen, a pharmaceutically acceptablesalt of the compound, wherein the agent is substantially pure.
 7. Thebiologically active agent of claim 6, selected from the group consistingof: 3-(2.6-Dimethylbenzyloxy)phenylacetic acid;6-[3-(2,6-Dimethylbenzyloxy)-phenyl]-hexanoic acid; Ethyl6-[3-(2,6-dimethylbenzyloxy)-phenyl]-hexanoate;5-[3-(2,6-Dimethylbenzyloxy)-phenyl]-pentanoic acid; Ethyl5-[3-(2,6-dimethylbenzyloxy)-phenyl]-pentanoate;3-[3-(2,6-dimethylbenzyloxy)phenyl]-propionic acid; and Ethyl3-[3-(2,6-dimethylbenzyloxy)phenyl]-propanoate.
 8. The biologicallyactive agent of claim 7, being 3-(2,6-Dimethylbenzyloxy)-phenylaceticacid.